The project will be based on further characterization and application of improved techniques to evaluate binding of agonist-ligands to presumed dopamine (DA) receptors in brain membranes. The in vitro biochemistry of binding of 3H-apomorphine (APO) and 3H-DA will be compared with that of 3H-haloperidol and 3H-spiroperidol. Effects of pH, ions, nucleotides, temperature; subcellular distribution; kinetics; pharmacology and structure-activity-relationships of DA agonists; biochemical evaluation of possible non-receptor "acceptor" sites; and attempts to modify binding sites by prior exposure to agonists will all be evaluated. The regional distribution of improved labeled agonist binding will be assessed throughout the central nervous system (CNS), and in selected peripheral tissues believed to contain DA receptors; development and effects of aging on DA receptors evaluated by ligand binding and by DA-sensitive adenylate cyclase activity will be studied along with sex differences in rodents; possible diurnal changes in receptor kinetics will be evaluated; effects of selected lesions in the forebrain DA systems with 6-OH-DA and kainic acid will be reevaluated with improved techniques. Studies of rodent and beef tissue will be complemented with studies of ligand binding in postmortem human brain tissue. Binding technique will be used to demonstrate the possibility of assaying tissue levels of DA agnoists; this work will be backed up by a sensitive and specific radioenzymatic biochemical assay; these assays will be used to characterize the salients of apomorphine uptake and tissue distribution, seeking correlations between tissue levels and behavioral effects in rat, as evaluated by improved techniques. Alterations of agonist binding sites following prolonged exposure of rat to DA agonists will be evaluated, controlling carefully for variance in drug metabolism; interactions of lithium salts on agonist-induced altered DA receptor sensitivity will be assessed. Genetic studies will be initiated in mouse, seeking correlations between genetically determined differences among strains in behavior and ligand binding.